The present invention relates to certain novel compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. More particularly, it relates to compounds which exhibit activation, including dual agonist activity, to peroxisome proliferator-activated receptors gamma (PPARxcex3) and alpha (PPARxcex1) thereby enabling them to modulate the blood glucose and lipid levels in mammals.
Treatment of type 2 diabetes mellitus usually begins with a combination of diet and exercise, with progression to oral hypoglycaemics (e.g. sulfonylureas) and in more severe cases, insulin. In the last decade a class of compounds known as thiazolidinediones (e.g. U.S. Pat. Nos. 5,089,514, 4,342,771, 4,367,234, 4,340,605, 5,306,726) have emerged as effective antidiabetic agents that enhance the insulin sensitivity of target tissues (skeletal muscle, liver, adipose) in animal models of type 2 diabetes mellitus and also reduce lipid and insulin levels in these animal models.
It has been reported that thiazolidinediones are potent and selective activators of PPARxcex3 and bind directly to the PPARxcex3 receptor (J. M. Lehmann et. al., J. Biol. Chem. 12953-12956, 270 (1995)), providing evidence that PPARxcex3 is a possible target for the therapeutic actions of the thiazolidinediones.
PCT patent publication WO 97/31907 discloses certain novel compounds that bind to and activate PPARxcex3. These compounds are indicated to be useful for the treatment of type 2 diabetes mellitus and other diseases.
Activators of the nuclear receptor PPARxcex3, for example troglitazone, have been shown in the clinic to enhance insulin-action, reduce serum glucose and have small but significant effects on reducing serum triglyceride levels in patients with Type 2 diabetes. See, for example, D. E. Kelly et al., Curr. Opin. Endocrinol. Diabetes, 90-96, 5 (2), (1998); M. D. Johnson et al., Ann. Pharmacother., 337-348, 32 (3), (1997); and M. Leutenegger et al., Curr. Ther. Res., 403-416, 58 (7), (1997).
The mechanism for this triglyceride lowering effect appears to be predominantly increased clearance of very low density lipoproteins (VLDL) through induction of liporotein lipase (LPL) gene expression. See, for. example, B. Staels et al., Arterioscler. Thromb., Vasc. Biol., 1756-1764, 17 (9), (1997).
Fibrates are a class of drugs which may lower serum triglycerides 20-50%, lower LDLc 10-15%, shift the LDL particle size from the more atherogenic small dense to normal dense LDL, and increase HDLc 10-15%. Experimental evidence indicates that the effects of fibrates on serum lipids are mediated through activation of PPARxcex1. See, for example, B. Staels et al., Curr. Pharm. Des., 1-14, 3 (1), (1997). Activation of PPARxcex1 results in transcription of enzymes that increase fatty acid catabolism and decrease de-novo fatty acid synthesis in the liver resulting in decreased triglyceride synthesis and VLDL production/secretion. In addition, PPARxcex1 activation decreases production of apoC-III. Reduction in apoC-III, an inhibitor of LPL activity, increases clearance of VLDL. See, for example, J. Auwerx et al., Atherosclerosis, (Shannon, Irel.), S29-S37, 124 (Suppl), (1996).
In addition, a dual agonist of PPARxcex1 and PPARxcex3 could be effective in reducing the dyslipidemia and hyperinsulinemia associated with impaired glucose tolerance (IGT) or metabolic syndrome and could be effective in patients with mixed hyperlipidemia. See, for example, U.S. Pat. Nos. 5,478,852.
PCT patent publication WO 98/05331 (Paterniti et al.) relates to methods for treating diabetes and cardiovascular disease using a PPARxcex3 agonist in combination with a PPARxcex1 agonist, or a compound that activates both PPARxcex3 and PPARxcex1.
Briefly, in one aspect, the present invention provides compounds of formula (I), and tautomeric forms, pharmaceutically acceptable salts and solvates thereof, 
wherein;
R1 is hydrogen or C1-3alkyl;
R2 is hydrogen, or C1-8alkyl optionally substituted by one or more halogens;
R3 is C1-6alkyl, C4-7cycloalkyl or cycloalkenyl, xe2x80x94OC1-6alkyl, xe2x80x94NRxe2x80x2Rxe2x80x2 (where each Rxe2x80x2 is independently hydrogen or C1-3alkyl), a 5 or 6 membered heterocyclic group containing at least one oxygen, nitrogen, or sulfur ring atom (optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, xe2x80x94OC1-6alkyl optionally substituted by one or more halogens, xe2x80x94CN, or xe2x80x94NO2), or phenyl (optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, xe2x80x94OC1-6alkyl optionally substituted by one or more halogens, xe2x80x94CN, or xe2x80x94NO2);
R4 is a 5 or 6 membered heterocyclic group containing at least one oxygen, nitrogen, or sulfur ring atom (optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, xe2x80x94OC1-6alkyl optionally substituted by one or more halogens, xe2x80x94CN, or xe2x80x94NO2), or phenyl (optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, xe2x80x94OC1-6alkyl optionally substituted by one or more halogens, xe2x80x94NRxe2x80x2Rxe2x80x2 (as defined above), xe2x80x94CN, or xe2x80x94NO2);
R5 is hydrogen, halogen, or C1-3alkyl optionally substituted by one or more halogens;
R6 is hydrogen or C1-3alkyl;
X is O or S; and
n is 1, 2, or 3.
Preferably, the compounds of this invention activate both the hPPARxcex3 and hPPARxcex1 receptors.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention. As used herein, xe2x80x9ca compound of the inventionxe2x80x9d means a compound of formula (I) or a tautomeric form, pharmaceutically acceptable salt, or solvates thereof.
The invention further provides a compound of the invention for use in therapy, and in particular, in human medicine.
In another aspect, the present invention provides a method for treatment or prevention of a hPPARxcex3 and/or hPPARxcex1 mediated disease, risk factor, or condition, comprising administration of a therapeutically effective amount of a compound of this invention.
According to another aspect, the present invention provides the use of a compound of the invention for the manufacture of a medicament for the is treatment or prevention of a hPPARxcex3 and/or hPPARxcex1 mediated disease.
hPPARxcex3 and/or hPPARxcex1 mediated diseases, risk factors, or conditions include hyperglycemia, dyslipidemia, type II diabetes mellitus including associated diabetic dyslipidemia, type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, hyperlipidemia, hypercholesteremia, hypertension, cardiovascular disease, including atherosclerosis, regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa. In particular, the compounds of the present invention are useful in the treatment or prevention of hyperglycaemia, dyslipidemia, and type II diabetes mellitus including associated diabetic dyslipidemia.
Preferably, R1 is hydrogen or methyl. Most preferably, R1 is hydrogen.
Preferably, R2 is C1-8alkyl optionally substituted by one or more halogens. Preferably, said halogen is fluorine. Most preferably, R2 is straight-chain.
Preferably, R3 is pyridine, pyrazine, thiophene, furan, thiazole, or phenyl (any of which may be optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, xe2x80x94OC1-6alkyl optionally substituted by one or more halogens, xe2x80x94CN, or xe2x80x94NO2), or C4-7cycloalkyl. Most preferably, R3 is phenyl (optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, xe2x80x94OC1-6alkyl optionally substituted by one or more halogens, xe2x80x94CN, or xe2x80x94NO2).
Preferably R4 is phenyl (optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, or xe2x80x94OC1-6alkyl optionally substituted by one or more halogens). Preferably, said halogen is fluorine. Most preferably R4 is phenyl either unsubstituted or substituted with 1, 2, or 3 fluorine atoms.
Preferably, R5 is hydrogen, halogen, or C1-3alkyl optionally substituted by one or more halogens. Most preferably R5 is hydrogen.
Preferably R6 is methyl or ethyl.
Preferably n is 2.
Preferably, the carbon atom bonded to CO2R1 is in the S configuration. In other words, preferably, the absolute configuration around that carbon is: 
Suitable compounds of the present invention include:
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4 -(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(4-fluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,3,4-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-(4-nitrophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,4,5-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-{(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-([2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-(4-methylphenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)-2-({[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-{[(Z)-1-butyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(4-chlorophenyl)-1-methyl-3-oxo-1-propenyl]amino{-3-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-(3-nitrophenyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-({(Z)-3-[2-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-3-oxo-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(4-isopropoxyphenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(2-chlorophenylyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(2-furyl)-1-methyl-3-oxo-1-propenylamino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2-pyrazinyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(2,4-difluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(1,3-thiazol-2-yl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(3-thienyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2-pyridinyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(2-fluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(2,3-difluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(2-hydroxyphenyl-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-propyl-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-3-(4-methoxyphenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-3-cyclohexyl-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-(4-{2-[2-(4-isopropoxyphenyl)-5methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-1-heptyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-(3-methylphenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4 -methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{-[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoic acid
(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(2-phenyl-5-propyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3oxo-3-phenyl-1-propenyl]amino}-3-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoic acid
(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[(2-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-{[(Z)-3oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoic acid
(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[(5ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoic acid
(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{[5ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[(5ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoic acid, and pharmaceutically acceptable salts and solvates thereof.
Preferred compounds of the invention include
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,3,4-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-(4-nitrophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,4,5-trifluorophenyl)-1-propenyl]amino}-3-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-{[(Z)-1-butyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(4-chlorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-propyl-1-propenyl]amino}propanoic acid
(2S)-3-{4-[2-(5methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoic acid
(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino{-3-4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoic acid
(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl)-2-{[(Z)-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[2-(5ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2[(Z)-3-oxo-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl )-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy)}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)1-propenyl]amino}propanoic acid
(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoic acid
(2S)-3-(4-{3-[5-ethyl-2-4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-y)propoxy]pheny}-l2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{[5ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yL)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid and pharmaceutically acceptable salts and solvates thereof.
Many of the compounds of formula (I) are dual activators of hPPARxcex3 and hPPARxcex1 As used herein, by xe2x80x9cactivating compoundxe2x80x9d, or xe2x80x9cactivatorxe2x80x9d, or the like, is meant those compounds which achieve at least 50% activation of human PPARxcex3 (xe2x80x9chPPARxcex3xe2x80x9d) or hPPARxcex1 (relative to the appropriate indicated positive control) in the transfection assay described below at concentrations of 10xe2x88x927 M or less. As used herein, a xe2x80x9cdual activatorxe2x80x9d is a compound that is an activator of both PPARxcex3 and PPARxcex1.   The  ⁢      xe2x80x83    ⁢  ratio  ⁢      xe2x80x83    ⁢                    EC        50            ⁢              xe2x80x83            ⁢      hPPAR      ⁢              xe2x80x83            ⁢      α                      EC        50            ⁢              xe2x80x83            ⁢      hPPAR      ⁢              xe2x80x83            ⁢      γ      
defines the relative activity of hPPARxcex1 to hPPARxcex3. Preferably, the dual activators of this invention have a relative hPPARxcex1 to hPPARxcex3 activity of from 0.02 to 50.
Those skilled in the art will recognize that stereocenters exist in compounds of formula (I). Accordingly, the present invention includes all possible stereoisomers and geometric isomers of formula (I) and includes not only racemic compounds but also the optically active isomers as well. When a compound of formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or any convenient intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds by E. L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen. Additionally, in situations where tautomers of the compounds of formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds.
It will also be appreciated by those skilled in the art that the compounds of the present invention may also be utilized in the form of a pharmaceutically acceptable salt or solvate thereof. The physiologically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable s acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts. References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
The terms C1-3alkyl, C4-6cycloalkyl, C1alkylene, C2-6alkenyl and the like, as used herein, indicate groups that may contain the indicated range of carbon atoms, for example 1 to 3 carbon atoms. Unless otherwise indicated, such groups can be straight chained or branched.
The term 5- or 6-membered heterocyclic group as used herein includes 5- or 6-membered substituted or unsubstituted heterocycloalkyl and heteroaryl groups, e.g. substituted or unsubstituted imidazolidinyl, piperidyl, piperazinyl pyrrolidinyl, morpholinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl or tetrazolyl. Particularly preferred heterocycles are pyridine, pyrazine, thiophene, furan, and thiazole.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
While it is possible that compounds of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. Accordingly, the present invention further provides for a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients.
Formulations of the present invention include those especially formulated for oral, buccal, parenteral, transdermal, inhalation, intranasal, transmucosal, implant, or rectal administration, however, oral administration is preferred. For buccal administration, the formulation may take the form of tablets or lozenges formulated in conventional manner. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulfate. The tablets may be coated according to methods well-known in the art.
Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid. Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
Additionally, formulations of the present invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use.
The formulations according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (as an emulsion in an acceptable oil, for example), ion exchange resins or as sparingly soluble derivatives as a sparingly soluble salt, for example.
The formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.
There is further provided by the present invention processes for the preparation of compounds of the invention Unless otherwise indicated, Rxe2x80x2, R1, R2, R3, R4, R5, R6, n, and X are as defined above.
A compound of structural formula (I) may be prepared from the condensation of a compound of formula (II): 
with a compound of formula (III), for example, in a polar organic solvent, such, 
as methanol, at temperatures from xe2x88x9220xc2x0 C. to 150xc2x0 C., such as 65xc2x0 C., in the presence of a dehydrating agent such as trimethylorthoformate and/or molecular sieves.
Alternatively, a compound of formula (I) where R5 is hydrogen may be prepared by reaction of a compound of formula (II) with a compound of: 
formula (IVa) in an organic solvent such as methanol at temperatures from xe2x88x9220xc2x0 C. to 150xc2x0 C., such as 65xc2x0 C., in the presence of a base, such as diisopropylethylamine.
Compounds of Formula (I) where R2 is CF3 may be prepared from the reaction of compounds of formula (II) with compounds of formula (IVb) in an organic solvent such as methanol at temperatures from xe2x88x9220xc2x0 C. to 150xc2x0 C., such as 23xc2x0 C., in the presence of a base such as diisopropylamine.
Compounds of formula (II) may be prepared via alkylation of compounds of formula (V), preferably where R1 is hydrogen, with compounds of formula (VI), where Rxe2x80x3 is an activating group such as mesylate followed by: 
deprotection of the amine under acidic conditions such as 4.0 N HCl in dioxane solution at 20xc2x0 C., or trifluoroacetic acid in dichloromethane at 20xc2x0 C.
Alternatively, compounds of formula (II) may be prepared from reaction of compounds of formula (V), preferably where R1 is methyl, with compounds of formula (VI), preferably where Rxe2x80x3 is hydrogen, in an organic solvent such as toluene at temperatures from xe2x88x9220xc2x0 C. to 150xc2x0 C. such as 20xc2x0 C. in the presence of triphenylphosphine and diethylazodicarboxylate in a Mitsunobu type procedure. Standard methyl ester hydrolysis conditions such as lithium hydroxide in tetrahydrofuran and water at 20xc2x0 C. followed by amine deprotection as hereinbefore described (see also Greene, T. W. and Wutz, P. G. M. xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d 2nd edition, 1991, John Wiley and Sons for a general discussion on protective group installation/removal) provides compounds of structural formula (II).
Compounds of formula (V) are commercially available and may also be prepared by someone skilled in the art from commercially available compounds.
Compounds of formula (VI), for example where Rxe2x80x3 is mesylate, may be prepared by reaction of an alcohol of formula (VI) where Rxe2x80x3 is hydrogen, with methanesulfonyl chloride in an organic solvent such as tetrahydrofuran at temperatures from xe2x88x9220xc2x0 C. to 150xc2x0 C. such as 0xc2x0 C. in the presence of an amine base such as triethylamine.
Alcohols of formula (VI) where Rxe2x80x3 is hydrogen, may be prepared via reduction of the corresponding carboxylic acid or ester of formula (IX) in an organic solvent such as diethyl ether at temperatures of from xe2x88x9220xc2x0 C. to 100xc2x0 C., such as 0xc2x0 C., in the presence of a metal hydride reagent such as lithium aluminum hydride. These acids or esters of formula (IX) may be prepared by a two stage alkylation/cyclization process between an amide or thioamide compound of formula (VII), and a bromoketoester compound of formula (VII), where Rxe2x80x2xe2x80x3 is alkyl. The alkylation/cyclization reaction may be performed in an organic solvent such as toluene or ethanol at temperatures of from xe2x88x9220xc2x0 C. to 200xc2x0 C., such as 110xc2x0 C., in the presence of a base such as triethylamine. For the preparation of (VIII), see: Chem. Pharm. Bull. (1986), 34(7), 2840-51, J. Med. Chem. (1992), 35(14), 2617-26, patent WO 9731907. 
Amides or thioamides of formula (VII) are commercially available or may be prepared from readily available compounds by one skilled in the art.
Compounds of formula (III) are commercially available or may be readily prepared by one skilled in the art, for example, by reacting a ketone of formula (X) with an ester of formula (XII), or by reacting a ketone of formula (XIII) with an ester of formula (XI), by reaction in an organic solvent, such as tetrahydrofuran, at temperatures from xe2x88x9220xc2x0 C. to 150xc2x0 C., such as 20xc2x0 C., in the presence of a base, such as sodium hydride, a metal cation scavenger, such as dibenzo-18-crown-6, and catalytic quantities of an alcohol, such as ethanol (See: Popic, V. V. et al. Synthesis 1991, 195-197). 
Compounds of formula (IVa) may be prepared from the addition of compounds of formula (XV) to compounds of formula (XIV) in an organic solvent such as tetrahydofuran at temperatures of from xe2x88x92100xc2x0 C. to 100 xc2x0 C. such as xe2x88x9278 xc2x0 C. followed by oxidation of the intermediate propargyllic alcohol with an oxidant, such as manganese dioxide, in an organic solvent, such as dichloromethane, at temperatures from xe2x88x9220xc2x0 C. to 100xc2x0 C., such as 20xc2x0 C. 
Alternatively, certain yne-one compounds of formula (IVa) may be prepared by dehydration of a compound of formula (III) where R5 is hydrogen in an organic solvent, such as dichloromethane, at temperatures from xe2x88x9220xc2x0 C. to 100xc2x0 C., such as 20xc2x0 C., in the presence of triphenylphosphine, bromine, and a base, such as triethylamine. When R2 is CF3, R5 is hydrogen, and R3 is phenyl, a compound of formula (III) in an organic solvent, such as dichloromethane, at temperatures from xe2x88x9220xc2x0 C. to 100xc2x0 C., such as 20xc2x0 C., in is the presence of triphenylphosphine, bromine, and a base, such as triethylamine yields a compound of formula (IVb). Compounds of formula (X), (XI), (XII), (XIII), (XIV), and (XV) are commercially available or may be prepared from readily available materials from one skilled in the art.
Suitable reaction conditions are described below and in the accompanying Examples. See also, for example, Chung et al., Selective Functionalization of (S)Tyrosine, Tetrahedron, 49(26), pp. 5767-5776, (1993), Solar et al., Selective O-Alkylation of Tyrosine, Journal of Organic Chemistry, 31, pp 1996-1997 (1966), O. Mitsunobu, Synthesis, p 1 (1981), and D. L. Hughes, Org. React. Vol. 42, p 335 (1992).
A compound of formula (I) can be converted to another compound of formula (I). A particular interconversion reaction involves conversion of a compound of formula (I) wherein Rxe2x80x2 represents C1-3alkyl, to a compound of formula (I) wherein Rxe2x80x2 represents hydrogen, suitably employing hydrolytic techniques e.g. an alkali metal hydroxide, in the presence of an ether solvent e.g. tetrahydrofuran and an alcoholic solvent e.g. methanol or the like. It will therefore be appreciated by persons skilled in the art that compounds which fall within general formula (I), may in some instances, be hereinafter described in the intermediate section, as they are useful for the preparation of other compounds of formula (I).
For any of the general processes and schemes described above, it may be necessary and/or desirable to protect sensitive or reactive groups. Protecting groups are employed according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley and Sons). These groups are removed at a convenient stage of synthesis using methods known from the art. Thus, for example, amino groups may be protected by a group selected from aralkyl (e.g. benzyl), acyl, or sulfonyl, e.g. allylsulfonyl, tert-butoxycarbonyl, phthalimide, or tosyl; subsequent removal of the protecting group being effected when desired by hydrolysis or hydrogenolysis as appropriate using standard conditions. Thus, for example, tert-butoxycarbonyl groups may be removed by hydrolysis under acidic conditions. Hydroxyl and carboxyl groups may be protected using any conventional hydroxyl or carboxyl protecting group. Examples of suitable hydroxyl and carboxyl protecting groups include groups selected from alkyl, e.g. methyl, tert-butyl, or methoxymethyl, aralkyl, e.g. benzyl, diphenylmethyl, or triphenylmethyl, heterocyclic groups such as tetrahydropyranyl, acyl. e.g. acetyl or benzoyl, and silyl groups such as trialkylsilyl, e.g. tert-butyldimethylsilyl. The hydroxyl protecting groups may be removed by conventional techniques. Thus, for example, alkyl, silyl, acyl, and heterocyclic groups may be removed by hydrolysis under acidic or basic conditions. Aralkyl groups such as triphenylmethyl may similarly be removed by hydrolysis under acidic conditions. Aralkyl groups such as benzyl may be cleaved by hydrogenolysis in the presence of a Noble metal catalyst such as palladium-on-charcoal. Silyl groups may also conveniently be removed using a source of fluoride ions such as tetra-n-butylammonium fluoride.
The following examples are set forth to illustrate the synthesis of some particular compounds of the present invention and to further exemplify particular applications of general processes described above. Accordingly, the following Example section is in no way intended to limit the scope of the invention contemplated herein.